The overall goal of this application is to build a multi-scale modeling platform for investigation of the breast cancer, with special emphasis on the roles of the tumor-initiating cells (TIC). This modeling platform will mainly consist of two closely related components: biological experiments and mathematical computational modeling. For the experiment component, we seek to use newly developed experimental and imaging methodologies to identify, localize, purify and characterize TIC. Further experiments will be designed to discover the spatial localization and movement, and specific changes in gene expression and cellular signaling of breast cancer TIC. Combined functional genomics and data mining strategies will allow us to characterize novel growth regulators. Further, our combined experimental and systems biology approach will allow us to evaluate responses to experimental therapeutics that may inhibit or kill TIC specifically in a manner not possible before. For the mathematical modeling component, we will develop bioinformatics and bio-imaging models to integrate and analyze the data generated from biological experiments, and make use of the information obtained from data analysis, biological knowledge to build in silico models to model TIC behavior, cancer cell apoptosis, cell migration, cycle and drug treatment response. Besides providing a basic framework for understanding the mechanism underlying breast cancer stem cell evolution, the models can also give birth to hypotheses or experimental design. More important, these models will allow one to predict the biological state under investigation and predict how the natural process will behave in various circumstances. Iterative feedback between these two components will refine our proposed platform further. The ultimate goal is an integrated modeling platform of breast cancer biology that can mimic in vivo processes faithfully enough to serve as a hypothesis-generation and screening tool, and in the distant future, as a tool for evaluating clinical procedures and their expected outcomes.